The pancreas produces many different hormones, as well as several substances important for digestion. To perform these roles, the pancreas contains different types of cells; for example, acinar cells make digestive enzymes that help to break down food. But, like other cells in the body, pancreatic cells can accumulate mutations in their DNA that cause them to divide, acquire an altered identity and form a cancerous tumor.

The DNA of cells is packed into a structure called chromatin. While the DNA sequence is essentially the same across all normal cells of a given individual, chromatin can be more or less compacted in the different cell types that comprise our body tissues. A collection of proteins called the SWI/SNF complex can reorganize the chromatin to change how tightly the DNA is packed. This determines which genes in the DNA are accessible and can be activated, and which ones cannot.

Around 25% of pancreatic cancers contain mutations in genes that produce proteins of the SWI/SNF complex. These mutations normally occur with an additional mutation that over-activates the gene that produces a potentially cancer-causing protein called Kras. Livshits et al. have now genetically engineered mice to investigate how one such SWI/SNF complex protein, called Arid1a, affects how pancreatic cancer develops using a genetic approach that made possible to temporarily halt the production of Arid1a in acinar cells by feeding these mice an antibiotic. The gene that produces Kras was also over-activated in the pancreases of the mice, making them more likely to develop cancer.

Within just two weeks of stopping the production of Arid1a, the acinar cells stopped producing digestive enzymes and started making other proteins that are typically found in cancerous cells, indicating that Arid1a is involved in maintaining the normal identity and activity of these cells. Restoring the ability of altered acinar cells to produce normal levels of Arid1a (by removing the mice from the antibiotic diet) did not reverse these changes. Biochemical experiments showed that acinar cells with reduced levels of Arid1a have altered chromatin. In particular, the genes that produce digestive enzymes, which are normally active in healthy pancreases, were less accessible in mice who had over-active Kras and reduced levels of Arid1a.

The results presented by Livshits et al. provide the first evidence of how alterations to Arid1a can lead to irreversible changes in the identity and activity of pancreatic acinar cells. These results will need to be carefully considered by researchers who are developing treatments for cancer patients with mutations in Arid1a and other SWI/SNF proteins. In particular, methods that attempt to restore the functions of absent SWI/SNF proteins to cancer cells are unlikely to treat the cancer successfully.

Aberrant chromatin regulation is a hallmark of cancer (Flavahan et al., 2017). Numerous studies have revealed an abnormal chromatin state in tumor cells in comparison with their tissue of origin, and mutations in genes encoding chromatin readers, writers and remodelers have been detected across the spectrum of human cancers (Feinberg et al., 2016). For example, subunits of the SWI/SNF ATP-dependent chromatin-remodeling complex show frequent mutation in many solid tumors (Bailey et al., 2016; Waddell et al., 2015; Witkiewicz et al., 2015), but understanding of the underlying biology and molecular mechanisms as to how these mutations influence cancer related processes remains limited.

SWI/SNF complexes regulate chromatin accessibility and thus gene expression by re-positioning nucleosomes and interacting with available transcription factors (TFs) at enhancer regions (Kelso et al., 2017; Mathur et al., 2017; Vierbuchen et al., 2017; Wang et al., 2017). While the predominance of apparently inactivating mutations in various SWI/SNF components implies a tumor-suppressive function for the complex, gene perturbation studies in mice have identified both pro- and anti-tumorigenic roles for individual SWI/SNF subunits. For instance, mice lacking Arid1a, the DNA-binding SWI/SNF subunit, in the colon develop adenocarcinomas (Mathur et al., 2017). However, opposing and stage dependent roles have been described within the same tissue, as Arid1a deletion can both impair and promote the initiation of liver tumorigenesis (Fang et al., 2015; Sun et al., 2017) and accelerates progression and metastasis in established disease (Sun et al., 2017). Another subunit, Smarca4, displays the opposite pattern in pancreatic tumorigenesis, where its deletion accelerates tumor onset but slows progression (Roy et al., 2015; von Figura et al., 2014a). Thus, the role of various SWI/SNF complex components in tumor initiation and progression can be context dependent.

As the SWI/SNF complex dictates chromatin accessibility by available TFs, such context dependencies might broadly relate to development or pathological cell state. Indeed, in drosophila and mammalian systems, SWI/SNF complex dependent regulation of gene expression controls cell identity and differentiation in developmental as well as regenerative contexts (Sun et al., 2016; Takada et al., 2016; Vieira et al., 2017). How loss of SWI/SNF subunit function contributes to changes in cell plasticity in concert with oncogenes that drive cancer development is poorly understood. Furthermore, it is not known whether the disruption of SWI/SNF activity that accompanies tumorigenesis is needed to sustain neoplastic disease.

We set out to develop an in vivo model to address the role of the SWI/SNF component ARID1A in pancreatic ductal adenocarcinoma (PDAC), a setting in which mutations in ARID1A or other SWI/SNF components occur in up to 25% of cancer patients (Shain et al., 2012). PDAC is nearly invariably initiated by activating mutations in the KRAS oncogene (Bailey et al., 2016), while additional mutations in tumor suppressor genes are accumulated in the course of PDAC progression (Hezel et al., 2006). PDAC can arise from mucinous precursor lesions, including the most common, pancreatic intra-epithelial neoplasia (PanIN), as well as intraductal papillary mucinous neoplasms (IPMN) and Mucinous Cystic Neoplasms (MCN), with activating KRAS mutations frequently found in these early neoplastic stages (Hosoda et al., 2017; Lee et al., 2016).

Tissue specific expression of mutant Kras in the developing and adult mouse pancreas recapitulates both the range of preneoplastic lesions and their progression to malignant PDAC (Hingorani et al., 2005; Izeradjene et al., 2007; Sano et al., 2014; Siveke et al., 2007). Lineage tracing studies indicate mutant Kras can drive PanIN development from acinar cells that undergo a process of persistent trans-differentiation termed acinar to ductal metaplasia (ADM) (Kopp et al., 2012). In this process, acinar cells lose their pyramidal morphology, downregulate expression of digestive enzymes and TFs characteristic of acinar cells, and turn on an embryonic progenitor-like transcriptional program that includes expression of ductal markers and development of glandular morphology (Storz, 2017). Deletion of key transcriptional regulators of acinar cell identity and regeneration such as Ptf1a, Nr5a2 and Pdx1, when combined with oncogenic Kras, accelerates ADM and PanIN development (Flandez et al., 2014b; Krah et al., 2015; Roy et al., 2016; Shi et al., 2009; von Figura et al., 2014b). Thus, maintenance of acinar cell identity and regenerative homeostasis provides an important barrier to tumorigenesis in PDAC.

Current mouse models of PDAC have limitations. For example, cancer sequencing studies imply that mutations can occur in biologically-relevant orders during tumorigenesis, yet traditional Cre/loxp-based mouse models necessarily recombine all conditional alleles simultaneously. Additionally, traditional gene ‘knockout’ models do not allow for the restoration of the endogenous protein, making it difficult to address questions of phenotypic reversibility and the requirement for sustained gene loss in disease maintenance. Addressing these issues, we implement a powerful mouse-modeling platform that enables inducible and reversible disruption of gene function to show that Arid1a depletion can modulate the early stages of pancreatic neoplasia in a context-specific manner that depends on the timing of Arid1a inactivation and the presence of oncogenic Kras. Remarkably, these cell state transitions facilitated by Arid1a perturbation involve reprogramming events that, in contrast to tissue regenerative responses, are irreversible.

Mutations in chromatin remodelers are prevalent across the human cancer spectrum, making identification of tissue specific relationships between chromatin regulation and tumorigenesis an important goal in understanding neoplastic progression. In this study, we used a rapid and robust mouse-modeling platform to study the consequences of inducible and reversible suppression of the Arid1a SWI/SNF subunit in a mouse model of pancreatic cancer. Suppression of Arid1a in adult acinar cells harboring oncogenic Kras mutations accelerates acinar to ductal reprogramming and specification of mucinous, pancreatic cancer precursor lesions that cannot be reversed by restoring endogenous Arid1a expression. Thus, our data suggest that Arid1a can provide a potent barrier to Kras driven acinar to ductal metaplasia and, consequently, early stage pancreatic neoplasia. Once disrupted by Arid1a mutation, these altered cells are reprogrammed in such a manner that Arid1a is no longer needed to sustain the aberrant cell fate.

The phenotype produced by Arid1a depletion in the presence of an oncogenic Kras mutation is characterized by reduced chromatin accessibility accompanied by loss of acinar morphology, reduced expression of acinar genes, and upregulation of a signature characteristic of mucinous lesions. These features imply that genomic areas rendered accessible by Arid1a harbor elements involved in preventing acinar to duct like trans-differentiation in the context of mutant Kras, a critical rate-limiting step in Kras driven pancreatic neoplasia. Indeed, our transcriptional and chromatin profiling data imply that Arid1a disruption, in the presence of oncogenic Kras, reduces the chromatin accessibility of key TFs to the enhancers of genes needed to sustain acinar cell fate. At least one such factor, Nr5a2, can physically interact with the SWI/SNF complex via the Baf60 subunit (Debril et al., 2004), suggesting a possible mechanism for aberrant Nr5a2 target deregulation upon Arid1a loss. Further studies will be necessary to determine the interplay between Nr5a2 and other acinar TFs that may underly the Arid1a-depletion phenotype.

The accelerated PanIN formation produced by Arid1a suppression required the presence of a Kras mutation, the initiating event in pancreatic carcinogenesis. Thus, Arid1a suppression in the normal pancreas did not appreciably perturb acinar differentiation, even during wound healing responses that force a reversible acinar to ductal metaplasia. Apparently, Arid1a suppression sensitizes pancreatic epithelial cells to mucinous reprogramming by oncogenic Kras or, alternatively, increases the efficiency of Kras-induced acinar-to-ADM-to-PanIN transitions. Regardless, this Kras-dependence differs from the phenotype produced by deletion of acinar TFs such as Ptf1a or Nr5a2, whose loss generally perturbs acinar maintenance and/or regeneration (Cobo et al., 2018; Flandez et al., 2014a; Krah et al., 2015; von Figura et al., 2014b). We hypothesize that the potent and cooperative effects between oncogenic signaling and chromatin remodeling at eroding barriers to cellular plasticity contributes to the high frequency of SWI/SNF component inactivation in many cancer types.

The enhanced PanIN phenotype observed in our model has intriguing differences and commonalities with other models harboring conditional deletions of different SWI/SNF components. Deletion of Brg1 during pancreatic development in conjunction with oncogenic Kras results in the formation of IPMN-like lesions contiguous with the native duct system that may derive from the ductal compartment rather than through ADM. Furthermore elimination of Brg1 in adult acinar cells prevents the development of Kras driven acinar to duct-like transdifferentiation and PanIN development (von Figura et al., 2014a). While a recent study employing conditional deletion of Arid1a in the pancreas also observed IPMN formation, PanIN formation was not suppressed, pointing towards distinct molecular consequences of targeting different SWI/SNF components (Kimura et al., 2018). The striking predominance of PanINs over IPMNs in our model may be due to a dosage effect, where IPMN formation requires complete loss of Arid1a in ductal progenitors or ductal cells, while acinar cells expressing mutant Kras are more highly dependent on Arid1a to maintain their identity, and thus are rapidly reprogrammed to mucinous PanINs upon partial Arid1a suppression. This has important implications for human cancers, which exhibit a broad spectrum of Arid1a levels.

Unlike our Arid1a suppression strategy, mouse models using conditional alleles necessarily disrupt SWI/SNF concomitantly with Kras activation. Indeed, when we recapitulate such timing during embryonic development, we see a lower level of PanIN formation with shArid1a pancreata showing the retention of acinar cells, that contrasts with the effects of sequential suppression of Arid1a in acinar cells harboring pre-existing expression of mutant Kras. While the distinct molecular consequences of different SWI/SNF component mutations may contribute to phenotypic variability in other aspects of PDAC progression, these observations indicate that the timing of SWI/SNF perturbation can have a dramatic effect on tumorigenesis phenotypes. Whether the temporal effects of SWI/SNF action are a consequence of developmental stage or priming events produced by the prior presence of activated Kras remains to be determined. In any case, it seems likely that one or both processes influences the transcription factor milieu and, accordingly, the specific consequences of SWI/SNF disruption (Roy et al., 2015; Sun et al., 2017). Regardless of the precise mechanism, the fact that Arid1a suppression can produce distinct phenotypes depending on the timing of gene suppression has ramifications for studying the SWI/SNF complex in other cancer types and, more generally, for cancer modeling in the mouse. Indeed, human cancers evolve as a consequence of a stepwise accumulation of mutations rather than the acquisition of multiple mutations simultaneously. Consequently, some phenotypes attributed to particular gene mutation in mice may not always extrapolate to the human system – not because of species differences, but because of the differential consequences of the timing of genetic events. Efforts to combine different recombination systems (e.g. Cre/Loxp and Flp/Frt) provide one way to uncouple events (Akagi et al., 1997; Orban et al., 1992). Additionally, our approach, which uses Cre-specific recombination to produce some oncogenic events and the tetracycline system to dictate timing of others, provides another. Such models may develop tumors with progression kinetics or therapeutic sensitivity profiles that more closely resemble those of patients.

Another unique advantage of our mouse modeling system is its ability to evaluate the reversibility of loss-of-function phenotypes, an approach that helps elucidate whether a cancer promoting event is required to sustain established disease. Indeed, the inducible shRNA technology used herein has been optimized to produce gene suppression that approaches that produced by gene deletion (Bolden et al., 2014; Dow et al., 2015; Ebbesen et al., 2016; Hemann et al., 2003; Premsrirut et al., 2011) yet, by leaving the target locus intact, enables the endogenous protein to be re-expressed upon shRNA silencing. Here, shRNA mediated knockdown of Arid1a produced a shift in acinar to mucinous cell fate and a PanIN histopathology that was not reversed by subsequent Arid1a re-expression. Such results suggest that ectopic overexpression studies in cell lines with mutations in SWI/SNF components may not reflect the biological activity of that component during tumor evolution. Furthermore, they stand in contrast to what has been noted for other tumor suppressor genes, for example, in colon cancer models where reversible APC suppression promoted the expansion of undifferentiated cells that readily underwent differentiation upon APC restoration (Dow et al., 2015). Since ARID1A controls the expression of thousands of gene targets via interaction with available TFs (Kadoch and Crabtree, 2015; Kelso et al., 2017; Mathur et al., 2017; Sun et al., 2016), it is possible that factors absent from mucinous lesions might be needed to reestablish an acinar transcriptional program when Arid1a is restored. Although Kras^G12D itself prevents acinar regeneration after pancreatitis-induced ADM, expression of the bHLH protein E47 in PDAC cells induces expression of digestive enzymes and activates a Mist1-based transcriptional network, indicating that such a reversion is possible (Kim et al., 2015).

Taken together, our data identify a role for Arid1a in the early stages of PDAC. This supports a model where initiating oncogenic KRAS mutations trigger ADM and PanIN conversion at low efficiency; mutation of ARID1A may boost the frequency of this process by increasing cellular plasticity. Other tumor suppressor mutations (such as TP53 and CDKN2A) that co-occur with KRAS and ARID1A can then contribute to further PanIN progression. While studies to explore the role of ARID1A in later stage PDAC progression are in progress, the irreversibility of the Kras-induced PanIN phenotype indicates that impaired SWI/SNF function may not be required for tumor maintenance. If confirmed, the identification of genotype-specific dependencies produced by SWI/SNF dysfunction rather than restoration of its normal activity may be a more effective way to exploit SWI/SNF mutations for new therapeutic approaches. While some proposed vulnerabilities, such as ARID1B, extend across multiple tissues and mutational landscapes (Helming et al., 2014), our data imply that many such dependencies are likely to be limited to a particular cell type or co-mutation context, due to the high degree of context specificity of Arid1a function in regulating cell identity and plasticity.

Sequencing data have been deposited in GEO under accession numbers GSE114576 and GSE114567.

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Author details

1. Geulah Livshits

   Department of Cancer Biology and Genetics, Memorial Sloan Kettering Cancer Center, New York, United States

   Contribution

   Conceptualization, Formal analysis, Funding acquisition, Investigation, Visualization, Writing—original draft, Writing—review and editing

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-3835-7377

2. Direna Alonso-Curbelo

   Department of Cancer Biology and Genetics, Memorial Sloan Kettering Cancer Center, New York, United States

   Contribution

   Data curation, Formal analysis, Validation, Investigation, Methodology, Writing—original draft, Writing—review and editing

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0001-6674-3059

3. John P Morris IV

   Department of Cancer Biology and Genetics, Memorial Sloan Kettering Cancer Center, New York, United States

   Contribution

   Resources, Formal analysis, Validation, Methodology, Writing—review and editing

   Competing interests

   No competing interests declared

4. Richard Koche

   Center of Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, United States

   Contribution

   Software, Formal analysis, Validation, Investigation

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-6820-5083

5. Michael Saborowski

   Department of Gastroenterology, Hepatology, and Endocrinology, Hannover Medical School, Hannover, Germany

   Contribution

   Resources, Methodology

   Competing interests

   No competing interests declared

6. John Erby Wilkinson

   Department of Pathology, University of Michigan School of Medicine, Ann Arbor, United States

   Contribution

   Formal analysis, Validation, Investigation

   Competing interests

   No competing interests declared

7. Scott W Lowe

   1. Department of Cancer Biology and Genetics, Memorial Sloan Kettering Cancer Center, New York, United States
   2. Howard Hughes Medical Institute, New York, United States

   Contribution

   Conceptualization, Resources, Supervision, Methodology, Project administration, Writing—review and editing

   For correspondence

   lowes@mskcc.org

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-5284-9650

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