PROOF OF CONCEPT

Dysregulated Golgi homeostasis has emerged as a potential contributor to tumor development and progression by altering the surface and secreted proteome, as well as Golgi-specific modifications. In this proposal we aim to uncover the effects of Golgi stress and perturbed Golgi morphology on cancer cell behavior and their interactions with the immune cells. Our research objectives encompass three specific aims: First, characterizing Golgi stress-induced Golgi fragmentation in a diverse panel of cancer cell lines, shedding light on the mechanisms underlying this phenomenon.

Malignant tumors present a distinct challenge to the immune system as "altered self". Although there is a well-established crosstalk between the immune system and the tumor that has substantial implications for cancer therapy, the nature of the antigens that allow the immune system to distinguish cancer cells from non-cancer cells has long remained obscure.

In this study we found that localized delivery of a type I Interferon (IFNβ) to a severe mouse melanoma model (B16F10) by injecting an adeno-associated-virus (AAV) as delivery system directly into the tumor we sensitize animals to respond favorably to anti-PDL1 immunotherapy.

Colorectal cancer (CRC) constitutes one of the leading causes of cancer-related deaths worldwide, which
typically insidiously develops through a long years-long process involving mutations accumulating in
different genes that are essential to a variety of cellular pathways such as WNT, RAS?MAPK, TGF-?, P53,
and DNA mismatch-repair pathways. The gut microbiome has been suggested to causally impact CRC
development, progression, and response to treatment. However, the mechanisms by which gut microbial

Cancer metastasis is a process in which cancer cells disseminate from the primary tumor, settle and grow at a site other than the primary tumor site. Cancer mortality primarily stems from metastatic recurrence, emphasizing the urgent need for developing effective metastasis-targeted immunotherapies. Metastatic breast cancer still accounts for a substantial portion of breast cancer-related deaths, with a median survival time of about 12 months after metastasis.

Cancer-associated cachexia is a multifactorial syndrome defined by weight loss and skeletal muscle atrophy, causing decreased quality of life, reduced treatment tolerance, and increased mortality. Although approximately 30% of all cancer deaths are directly caused by cachexia, there is no reliable treatment. We recently demonstrated that an early metabolic rewiring in liver metabolism promoted by the innate immune system contributes to the manifestations of cancer-associated cachexia.

Immunotherapy has sparked new hope for oncology due to its remarkable ability to induce a durable
response in patients with metastatic cancer. However, a large fraction of patients do not respond to
immunotherapy. The immune response against tumor cells is driven by neoantigen presentation. Yet, most
tumors harbor a low mutational burden, limiting their targetable neo-peptidomic space. We propose to

Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy, often diagnosed in advanced and inoperable stage. Diagnosis requires histologic confirmation, typically obtained through endoscopic ultrasound (EUS) and endoscopic retrograde cholangiopancreatography (ERCP). These procedures are invasive and pose significant risks to patients. Recent discoveries in our lab have shown that shed cells from luminal washes carry information about their tissue of origin.

In cancer care, patients undergoing chemotherapy are required to manage their illness independently. Such management involves following the doctor's instructions and making critical decisions that affect their survival, such as reporting side effects or going to the emergency room. This research aimed to identify the types of knowledge patients need to manage their symptoms and side effects effectively.