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Immunoglobulin A (IgA) is the major secretory immunoglobulin isotype found at mucosal surfaces, where it regulates microbial commensalism and excludes luminal factors from contacting intestinal epithelial cells (IECs). IgA is induced by both T cell-dependent and -independent (TI) pathways. However, little is known about TI regulation. We report that IEC endoplasmic reticulum (ER) stress induces a polyreactive IgA response, which is protective against enteric inflammation. IEC ER stress causes TI and microbiota-independent expansion and activation of peritoneal B1b cells, which culminates in increased lamina propria and luminal IgA. Increased numbers of IgA-producing plasma cells were observed in healthy humans with defective autophagy, who are known to exhibit IEC ER stress. Upon ER stress, IECs communicate signals to the peritoneum that induce a barrier-protective TI IgA response.

Immunoglobulin A (IgA) is the major secretory immunoglobulin isotype found at mucosal surfaces, where it regulates microbial commensalism and excludes luminal factors from contacting intestinal epithelial cells (IECs). IgA is induced by both T cell-dependent and -independent (TI) pathways. However, little is known about TI regulation. We report that IEC endoplasmic reticulum (ER) stress induces a polyreactive IgA response, which is protective against enteric inflammation. IEC ER stress causes TI and microbiota-independent expansion and activation of peritoneal B1b cells, which culminates in increased lamina propria and luminal IgA. Increased numbers of IgA-producing plasma cells were observed in healthy humans with defective autophagy, who are known to exhibit IEC ER stress. Upon ER stress, IECs communicate signals to the peritoneum that induce a barrier-protective TI IgA response.

Colorectal cancer development is characterized by successive acquisition of key oncogenic mutations in cellular grow factor signaling pathways that drive malignant transformation from healthy intestinal epithelium to cancer. Understanding colorectal cancer development requires knowledge on the fundamental cellular processes that are altered, breached or exploited by these mutations. This dissertation, containing eight chapters of basic cell biological research, discusses how the presence of oncogenic driver mutations in intestinal epithelial cells affects various hallmarks of cancer, by interfering with fundamental cell biological functions that include global mRNA synthesis and adaptation to endoplasmic reticulum stress. To study this, we made use of several murine and human genetically manipulated organoid models of colorectal cancer that harbor mutations in APC, KRAS, SMAD4 and TP53. In addition, we used genetic mouse models and associated ex vivo organoid culture models to investigate modulation of the endoplasmic reticulum stress response in the context of a healthy and malignant intestinal epithelial cell. Taken together, this work may deeper our understanding of underlying mechanisms of malignant transformation. It also exposes factors in pathway related to regulation of global mRNA translation that may be used to modulate aberrant biological cell behavior, which could provide opportunities for development of targeted anti-cancer therapy.

Stressed gut epithelium gets some relief Immunoglobulin A (IgA) is the most abundantly expressed antibody isotype and can be found at various mucosal surfaces in the body, including the gastrointestinal (GI) tract. IgA is polyreactive and can coat and restrain both commensal bacteria and enteric pathogens. Grootjans et al. found that endoplasmic reticulum (ER) stress in the intestinal epithelial cells of mice induced the T cell– and microbiota-independent expansion of peritoneal B1b cells, which secrete IgA. Similarly, human subjects homozygous for a variant of an autophagy gene ( ATG16L1 ) known to cause ER stress showed increased numbers of GI IgA + cells compared with controls. Thus, epithelial ER stress serves as an advantageous “eustress” response that can functionally antagonize its well-characterized role in promoting inflammation. Science , this issue p. 993

Colorectal cancer (CRC) is one of the leading causes of cancer related deaths worldwide. Surgical resection is the primary treatment modality, but can only be curative in the earliest stages of CRC. As these early stages often occur asymptomatically, much effort is being put into earlier detection by population based screenings. Nonetheless, the vast majority of diagnosed CRCs will need additional chemo-radiation therapy. Although more and more specific anti-cancer therapies are being developed, the standard of care remains treatment with cytotoxic agents that target both cancer and healthy cells resulting in severe toxicity. In this thesis, we have investigated factors that influence the initiation of colorectal cancer (CRC), as well as mechanisms that manipulate resistance to conventional chemotherapy in established CRC. Increasing our knowledge of both processes is instrumental to combat cancer better. Collectively, our results put forward novel candidates that play critical roles in these processes and may therefore serve as attractive targets in the development of new therapies that may ultimately prevent or treat CRC.

The aim of this thesis is to further unravel the pathways and genes responsible for epithelial homeostasis in the mouse esophagus. Whereas a single layer of columnar epithelium lines most of the gastrointestinal tract, the esophagus is covered with a multilayered squamous epithelium. Proliferative cells reside within the basal layer from which they move upwards and differentiate. Upon reaching the lumen cells are shed off to travel in the direction of the stomach. We still have very limited insight in pathways and genes involved in normal homeostasis of the esophageal epithelium. Enhancing our knowledge of the mechanisms of proliferation and pathways driving differentiation is therefore crucial. It would lead to better understanding of esophageal carcinogenesis, development of Barrett esophagus and tissue repair. The existence of the stem cell in esophagus has thus far been disputed and all cells in the basal layer have been attributed stem cell properties. As this notion contradicts our understanding of the biology of almost all other epithelial tissues, further experimental evidence is needed to clarify the involvement of stem cells in esophageal homeostasis. This effort is especially worth given an implication of stem cells in oncogenic transformation and development of esophageal cancer. To date, a limited number of studies has been performed to address the pathways and genes in control of esophageal epithelial proliferation and differentiation. In the first part of this thesis the role of Hedgehog signaling in the mouse esophagus and intestine is described. The second part of this thesis revolves around the role of ER stress on the esophageal epithelium.