Objective: Here, we evaluate the contribution of AT-rich interaction domain-containing protein 1A ( ARID1A ), the most frequently mutated member of the SWItch/sucrose non-fermentable (SWI/SNF) complex, in pancreatic homeostasis and pancreatic ductal adenocarcinoma (PDAC) pathogenesis using mouse models. Design: Mice with a targeted deletion of Arid1a in the pancreas by itself and in the context of two common genetic alterations in PDAC, Kras and p53 , were followed longitudinally. Pancreases were examined and analysed for proliferation, response to injury and tumourigenesis. Cancer cell lines derived from these models were analysed for clonogenic, migratory, invasive and transcriptomic changes. Results: Arid1a deletion in the pancreas results in progressive acinar-to-ductal metaplasia (ADM), loss of acinar mass, diminished acinar regeneration in response to injury and ductal cell expansion. Mutant Kras cooperates with homozygous deletion of Arid1a , leading to intraductal papillary mucinous neoplasm (IPMN). Arid1a loss in the context of mutant Kras and p53 leads to shorter tumour latency, with the resulting tumours being poorly differentiated. Cancer cell lines derived from Arid1a -mutant tumours are more mesenchymal, migratory, invasive and capable of anchorage-independent growth; gene expression analysis showed activation of epithelial-mesenchymal transition (EMT) and stem cell identity pathways that are partially dependent on Arid1a loss for dysregulation. Conclusions: ARID1A plays a key role in pancreatic acinar homeostasis and response to injury. Furthermore, ARID1A restrains oncogenic KRAS-driven formation of premalignant proliferative IPMN. Arid1a -deficient PDACs are poorly differentiated and have mesenchymal features conferring migratory/invasive and stem-like properties.

Cholangiocarcinoma (CCA) is a deadly and heterogeneous type of cancer characterized by a spectrum of epidemiologic associations as well as genetic and epigenetic alterations. We seek to understand how these features inter-relate in the earliest phase of cancer development and through the course of disease progression. For this, we studied murine models of liver injury integrating the most commonly occurring gene mutations of CCA – including Kras, Tp53, Arid1a and Smad4 – as well as murine hepatobiliary cancer models and derived primary cell lines based on these mutations. Among commonly mutated genes in CCA, we found that Smad4 functions uniquely to restrict reactive cholangiocyte expansion to liver injury through restraint of the proliferative response. Inactivation of Smad4 accelerates carcinogenesis, provoking pre-neoplastic biliary lesions and CCA development in an injury setting. Expression analyses of Smad4-perturbed reactive cholangiocytes and CCA lines demonstrated shared enriched pathways, including cell-cycle regulation, MYC signaling and oxidative phosphorylation, suggesting that Smad4 may act via these mechanisms to regulate cholangiocyte proliferation and progression to CCA. Overall, we showed that TGFβ/SMAD4 signaling serves as a critical barrier restraining cholangiocyte expansion and malignant transformation in states of biliary injury.

Background/Objectives: Total neoadjuvant therapy (TnT) has emerged as a treatment option for locally advanced rectal cancer. Few studies have evaluated specifically the use of chemotherapy and short-course radiation therapy (SCRT) in obtaining a complete clinical response (cCR) or near-complete clinical response (nCR) and offering non-operative management (NOM). This phase II study sequences FOLFOX followed by SCRT with the primary aim of evaluating the rate of cCR or nCR. Methods: Treatment-naïve adults with non-metastatic clinical T2-3N0 or T1-3 with N1-2a rectal adenocarcinoma deemed candidates for total mesorectal excision (TME) were eligible for this open-label, single-arm clinical trial. This trial evaluated TnT with 5-fluorouracil, leucovorin and oxaliplatin (mFOLFOX6) followed by SCRT. The primary endpoint was the rate of cCR or nCR. Those with cCR or nCR after TnT were offered NOM and close surveillance; all others underwent TME. Secondary endpoints included 1-year disease-free survival (DFS), overall survival (OS), and R0 surgical resection rate. Results: Twelve patients of a planned 40 were enrolled with a median follow-up duration of 4.1 years. The study was closed early after results of the OPRA trial suggested a benefit of sequencing radiation prior to chemotherapy when seeking organ preservation. Four of the twelve patients (33%, 95% CI = (9.9%, 65.1%)) achieved cCR or nCR after TnT and underwent NOM; one patient had local regrowth 5.5 months after the completion of TnT and underwent TME. All four were free of disease at time of analysis. The 1-year DFS was 100%. The median OS was not reached. All surgical resections were R0 with no local recurrence after TME. Conclusions: This paper suggests that TnT with FOLFOX followed by SCRT is a safe and effective approach for treating locally advanced rectal cancer. This approach can be considered in select patients. The 33% of patients offered NOM is lower than the published 74% in OPRA, however, suggesting that chemotherapy followed by SCRT may not be the most optimal approach if organ preservation is the primary treatment aim.