Deciphering Tumor-Host Biology (2018-2023), a Toppforsk “top research grant” funded by
the Research Council of Norway and University of Oslo.
Through our long-standing interest in the lab in understanding the process of autophagy and
relevance to disease, we found that the lipid kinase, PIK3C3 complex acts as a tumor
suppressor to control epithelial integrity through the tumor suppressor kinase, LKB1 (OFarrell,
F., Lobert, V. et al, NCB, 2017). In a Drosophila tumor model where complex aspects of
carcinogenesis can be modeled, we uncovered that tumor cells induce an autophagy stress
response locally in the microenvironment and systemically in distant tissues. The local
autophagy response supports tumor growth, in part through providing amino acids (Katheder,
N., et al nature, 2017). In this “Toppforsk” project, we characterize
the reciprocal communication between tumor and host metabolically and transcriptionally in
order to infer the communication between tumor and host, both locally and systemically. We
develop novel genetic tools to enable independent manipulation of tumor and host tissues in
order to systematically interrogate what cellular mechanisms are required for tumormicroenvironment
interaction in order to support tumor growth and what are the
mechanisms for long-distance detrimental effects on systemic tissues, including cachexia.
Current avenues pursued include the role of inflammation and reactive oxygen species stress
signaling on tumor growth, cell competition, and systemic effects.
Mechanisms of tumor-induced wasting (2018-2021) funded by South-Eastern Norway
Regional Health Authority. 80% of late-stage cancer patients suffer severe cachectic muscle
and adipose tissue wasting. This condition is characterized by immune and metabolic
reprogramming that collectively and dramatically worsens prognosis, decreases quality of life,
prevents cytostatica treatment and accounts for more than 20% of cancer-related deaths. The
mechanisms of tumor-induced wasting remain obscure and there is currently no effective
treatment. We have found that tumors trigger peripheral organ stress responses (Katheder,
N., et al nature, 2017) in muscle and adipose tissue akin to that of cancer cachexia in humans.
The overall aim of this project is to functionally and mechanistically decipher tumor-host
interactions and cell biology underlying organ wasting. We have developed a novel stable
isotope tracing method to measure organic building block sources for tumor growth and show
that tumors source the majority of their building blocks from host and not food during growth
(Holland P, et al BMC Biology, accepted). Moreover, we have also found that organ (muscle)
atrophy is mediated by autophagy and lead to serum nutrient mobilization to “feed” the
tumor during cachexia-like wasting in Drosophila (Khezri, R., et al BioRxiv, under revision). We
currently study the role of lipid and sugar mobilization during cachexia and its effects on organ
wasting and tumorigenesis in trans.
Uncovering Nutrient Vulnerabilities to stall Tumor Growth in vivo (2021-2024, South-
Eastern Norway Regional Health Authority, and EMBO).
Tumors do not grow in isolation, but depend on extracellular nutrients for energy, redox
control, cellular signaling and building blocks in order to increase biomass and sustain cell
survival and proliferation. Upon transformation, tumor cells reprogram their metabolism for
growth, and at the same time creates tumor cell vulnerabilities that can be targeted. Herein
lies the proven potential to harvest the ability to interfere with nutrient access and
metabolism to stall tumor growth. In this project, initially funded by a EMBO long-term
postdoctoral fellowship to Swarupa Panda, we aim to uncover tumor metabolic vulnerabilities
in vivo under physiological conditions by way of targeting nutrient (SLC) transporters and
metabolism in preclinical animal cancer models (Drosophila and mouse Xenograft).
Two 3-year postdoctoral positions are open to study:
1. Tumor-Host interactions and Cancer cachexia utilizing our newly established system to independently generating tumors and manipulating systemic tissues using Gal4. This enables systematic interogation of systemic effects through targeted genetic screening. We are seeking a highly driven and experienced Drosophila expert for this project.
Application deadline May 15. Contact us as soon as pissble.
2. What are the nutrient requirements for tumor growth? This project will use human cell culture and mouse xenograft models. CRIPSR-Cas9 screening, Cell biology, Metabolism, biochemistry and metabiolism is central.
We are seeking an expert in metabolism, cell biology and/or SLC nutrient transporters for this project.