PhD position (Ageing & Disease): The role of B cells in Colorectal Cancer Development and Progression

Thinking of doing your PhD in the Life Sciences? The International PhD Programme (IPP) Mainz is offering talented students the chance to work at the cutting edge of research. As an IPP PhD student, you will join a community of exceptional scientists working on diverse topics ranging from how organisms age or how our DNA is repaired, to how epigenetics regulates cellular identity or neural memory.

Activities and responsibilities:

In the field of “Ageing & Disease”, the research group of Björn Clausen offers the following PhD project:

Colorectal cancer (CRC) is a leading cause of cancer-related deaths among men and women worldwide, with increasing incidence rates, in particular in young people. CRC can arise sporadically or due to chronic inflammation, and both genetic disposition as well as environmental factors contribute to the development of CRC. Risk factors include age and lifestyle such as poor dietary habits, alcohol consumption, smoking, obesity, and lack of physical activity, and possibly viral infections. Patients with long-standing inflammatory bowel diseases exhibit a higher risk to develop colitis-associated colorectal cancer (CAC).

B cells are an important part of the immune cell infiltrate of tumors, and their contribution to tumor initiation, development, and immunosurveillance is complex with both pro- and anti-tumorigenic effects. Recent studies implicate a fundamental role of B cells in shaping anti-tumor responses through several mechanisms. While IgA⁺ plasma cells regulate bacterial populations in the gut lumen in steady state, plasma cell-derived tumor-specific IgG1 antibodies mediate cell cytotoxicity and phagocytosis of tumor cells. In addition, B cells present tumor-specific antigens via MHCI and MHCII to T cells inducing their anti-tumor effector function. B cells also regulate the immune response within the tumor microenvironment through the release of cytokines, such as IFN-g, IL-12, or IL-10. CRC patients show substantial alterations in their B cell compartment, with increasing numbers of IL-10 producing B cells in advanced tumors and metastases. CRC patients with tumors highly infiltrated by CD20⁺ B cells display significantly improved survival, which suggests an anti-tumor role of B cells. In line, B cells are closely associated with CD8⁺ cytotoxic T cells, which are important in antigen-specific immunity against tumors. Antibody-independent mechanisms such as antigen presentation, cytokine production, direct cytotoxicity, and indirect effects through modulation of other immune cells have been demonstrated to be of great importance. Thus, whether B cells promote or inhibit tumor growth depends on different variables, such as temporal and spatial settings, as well as on the composition of B cell subsets. Therefore, a phenotypical and functional characterization of B cells in CRC tumor initiation and progression is of great interest with a possible therapeutic benefit.

PhD project: The role of B cells in Colorectal Cancer Development and Progression

The molecular and cellular mechanisms underpinning inflammatory processes that promote epithelial transition to carcinogenesis are still only insufficiently characterized, and especially how B cells contribute to these processes. We started investigating the role of B cells in the inflammatory phase, and at later time points of tumor development/progression in the well-established animal model of inflammation-induced CRC (AOM/DSS). We could show that B cells exert an important role by using B cell-deficient mice (JHT mice), which were completely resistant to AOM/DSS-induced inflammation as well as CRC development. Further, we could show that B cell-specific secretion of the immunosuppressive cytokine IL-10 drives CAC development, whereas it does not affect the inflammatory phase of CAC development.

In this proposed project, we will further elucidate the role of B cells in CAC using the AOM/DSS model. We will perform a detailed in vivo and in vitro analysis of different transgenic animals, manipulating, for example, antibody secretion using mice that are not able to secrete antibodies (IgMi mice). We will further use mice that allow us to delete B cells at any desired time point of CRC development to investigate the temporal/spatial role of B cells in colon carcinogenesis (iDTRCD19-cre mice).

In addition, we will employ a non-inflammatory model of sporadic CRC since preliminary data also show a significant role of B cells in this tumor entity. Besides these animal models, we will perform different molecular methods, flow cytometric analysis, immunohistochemistry as well as single cell and bulk RNA sequencing from tumors as well as the tumor microenvironment. We will create organoids, if possible, also from human tissue samples.

Finally, we will translate our experimental findings to the clinic by using human CRC samples from patients with inflammation-induced CRC in comparison to patients suffering from sporadic CRC and investigate the contribution of B cells.

Of note, this project is jointly conducted by the Hövelmeyer and Clausen laboratories at the Institute for Molecular Medicine in Mainz, as funded by the established DFG CRC 1292.

If you are interested in this project, please select Clausen (Canc) as your group preference in the IPP application platform.

What we offer:

• Exciting, interdisciplinary projects in a fully international environment, with English as our working language
• Advanced training in scientific techniques and professional skills
• Access to our state-of-the-art Core Facilities and their technical expertise
• Fully funded positions with financing until the completion of your thesis
• A lively community of more than 190 PhD students from 44 different countries

Requirements:

Are you an ambitious, young scientist looking to push the boundaries of science while interacting with colleagues from multiple disciplines and cultures? Then the IPP is your opportunity to give your scientific career a flying start!

All you need is:

• Master or equivalent
• Interactive personality & good command of English
• 2 letters of reference

For more details on the projects offered and how to apply via our online form, please visit https://www.imb.de/phd

The deadline for applications is 8 November 2023. Interviews will take place at IMB in Mainz on 22-24 January 2024.

Starting date: 1 March 2024 – 1 August 2024