Authors:

Anthony Striker

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The axolotl, Ambystoma mexicanum, is a neotenic salamander that has long served as a model in regenerative biology for its unique ability to regenerate almost any nonvital organ or complex structure. This phenomenon, fascinating in its implications for human regenerative medicine and tissue repair, should by all reasoning be accompanied by a great downside. Such mass proliferation events, through compounding probabilities and the need for rapid cell division, create an extraordinary potential for malignant tumours. Yet, shockingly, axolotls and other salamanders exhibit almost no cancer, with countably few cases recorded throughout their history of study. This rigorous control over cell cycle and fate, though often addressed, is barely studied from a molecular perspective, and understanding it could contribute greatly to both regenerative medicine and cancer biology. This study therefore aims to establish resources and methods to study molecular mechanisms of cancer defense and proliferation control in Axolotls. To this end, we are in the process of creating a line of Axolotls with a CRISPR-Cas9 knockout of the well-known tumor suppressor TP53, which has previously been implicated in regulating the process of urodele limb regeneration. This will help examine this gene's role, while hopefully creating the possibility of generating spontaneous axolotl tumors. Additionally, we are conducting trans- and explant experiments to investigate the role of a potentially altered self- nonself paradigm in axolotl immunity and immunosurveillance. These experiments will also include injections of cells, including transgenic cell lines and, if a stable cell line can be generated, rare spontaneous axolotl tumor isolate. We are also conducting in vitro experiments to determine the role of required exogenous signalling for regeneration-associated cell cycle control, such as prolactin and epinephrine. Preliminary results paint a picture of a regenerative environment in which the cell cycle is tightly regulated to both enable rapid proliferation and hinder malignancies. Identifying Causes of Cancer Treatment Resistance Through Spatial Transcriptomic Analysis of Tumor Microenvironment Signals Sudhish Swain, Martin Hemberg Harvard College | Kirkland House | Integrative Biology | 2028 Drug resistance, or the ability for cancer cells to become tolerant towards treatment methods, is associated with over 90% of cancer- related deaths and is one of the leading barriers to effective cancer treatment. Recent evidence suggests that the tumor microenvironment plays a critical role in regulating immune escape, progression, and distant metastasis of cancer. Hence, understanding how tumors evolve to resist common treatment methods via the tumor microenvironment is at the forefront of cancer research. Advances in molecular imaging technology have led to the release of spatial transcriptomic instruments like the CosMx and Xenium profilers. These machines allow for the simultaneous monitoring of a large number of RNA and protein targets while preserving the spatial context of cells and molecules within a tissue. By analyzing the cell-cell interactions of numerous cancer tissues' spatial transcriptomic data, we sought to uncover the mechanisms that underlie treatment resistance by investigating the differential gene expression of cancer cells when proximate versus distal (close versus far) to cancer-associated fibroblasts. Across multiple types of cancer cells, several ligand/receptor gene pairs were commonly differentially expressed depending on distance to nearest cancer-associated fibroblast. The downstream pathways of these genes are currently being investigated to understand how they promote tumor survival and immune evasion across multiple types of cancer to develop therapeutics that increase the efficacy of current treatments. Harvard Summer Undergraduate Research Village Program for Research in Science and Engineering

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Harvard / Molecular and Cellular Biology / 2028

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Co-authors:

Anthony Striker