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Department of Cancer Metabolomics

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Chief (Principal Investigator) Susumu Hirabayashi Researchmap
e-mail: shirabay
Research Scientist
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*Please add @po.kyoundo.jp after e-mail address

Overview

Cancer is increasingly viewed as a systemic metabolic disease associated with a range of host metabolic changes including obesity, insulin resistance, and cachexia (organ wasting syndrome), each of which alters the host systemic metabolic and nutritional environment. Cancer cells actively acquire nutrients from the extracellular space to support their growth, but how cancer cells sense and respond to changes in systemic nutrient availability in the context of metabolic disease remains an under-explored area in cancer biology. This is in part due to the complex interactions between cancer cells and their host tissues, which can only be studied in the whole-animal setting.

We leverage the fruit fly Drosophila melanogaster as a model system to investigate host-tumour metabolic/nutritional interactions. The ability to perform genetic tests in a whole-animal setting provides a powerful approach for studying host-tumour interactions and inter-organ communications. Our research aims to elucidate the molecular links between metabolic diseases and cancer, and to use this knowledge to develop novel therapeutic strategies that target these connections.

Projects

1. Understanding how obesity and diabetes promote tumor progression

We developed a Drosophila tumor model by co-activating the oncogenes Ras and Src in the epithelial tissue of the larval eye imaginal disc (the precursor to the adult compound eye). Under standard feeding conditions, these flies develop small benign tumors (Figure 1, left). Feeding flies a high-sugar diet leads to sugar-dependent metabolic defects including fat accumulation, insulin resistance, hyperglycemia, and hyperinsulinemia. Strikingly, feeding larvae a high-sugar diet transformed Ras/Src-activated clones from a localized benign tumours into aggressive overgrowths associated with tumour spread to other body regions (Figure 1, right). Using this model system, we are exploring how systemic metabolic changes associated with obesity and diabetes drive tumor progression.
Fig. 1: Tumors in Drosophila larvae fed a normal diet versus a high-sugar diet. Tumors were induced in the eye imaginal disc (boxed area) and marked with GFP (green). Under high-sugar conditions, tumors overgrew, metastasized, and formed secondary tumors (arrows). Dual labeling of tumors with GFP (green) and DAPI (red). Modified from Hirabayashi et al., Cell (2013).

2. Elucidating the effect of cancer cachexia on tumor progression

Our studies revealed that malignant Ras/Src tumors induced by a high-sugar diet also trigger cancer cachexia-like symptoms, notably systemic skeletal muscle wasting (Figure 2). This muscle wasting leads to increased levels of the amino acids, including proline, in the hemolymph (the insect equivalent of blood). Tumors exploit this by upregulating proline transporters, enabling increased proline uptake to support their own growth. These findings suggest that muscle wasting is not merely a secondary effect of cancer, but rather an active metabolic program that drives tumor progression. We are currently investigating how additional systemic metabolic changes associated with cancer cachexia contribute to tumor progression.
Fig. 1: Skeletal muscle remains intact in Drosophila with benign tumors under normal diet, but is significantly wasted when tumors become malignant under a high-sugar diet conditions. Skeletal muscles were labeled with actin (red) and myosin (green). Modified from Newton et al., Nature Communications (2020).

Publications

Last 5 years

  1. Martinez-Martinez D, Peres TV; Gehling K, Quintaneiro L, Cabrera C, Cherevatenko M, Cutty SJ, Best L, Marinos G, Zimmerman J, Safoor A, Chrysostomou D, Mokochinski JB, Montoya A, Brodesser S, Zatorska M, Scott T, Andrew I, Kramer H, Begum M, Zhang B, Golding BT, Marchesi JR, Hirabayashi S, Kaleta C, Barr AR, CFrezza C, Cochemé HM, and Cabreiro F: Chemotherapy Modulation by a Cancer-Associated Microbiota Metabolite. Cell Systems in press, 2025.
  2. Choutka C, Cabrera C, Hirabayashi S: Embracing complexity in Drosophila cancer models. Disease Models & Mechanisms 15: dmm049513, 2022.
  3. Newton H, Wang Y-F, Camplese L, Mokochinski JB, Kramer, HB, Brown AEX, Fets L, and Hirabayashi S: Systemic muscle wasting and coordinated tumour response drive tumourigenesis. Nature Communications 11: 4653, 2020.
  4. Alajati A, D’Ambrosio M, Troiani M, Mosole S, Pellegrini L, Chen J, Revandkar A, Bolis M, Theurillat J-P, Guccini I, Losa M, Calcinotto A, De Bernardis G, Pasquini E, D’Antuono R, Sharp A, Figueiredo I, Rodrigues D, Welti J, Gil V, Yuan W, Vlajnic T, Bubendorf L, Chiorino G, Gnetti L, Torrano V, Carracedo A, Camplese L, Hirabayashi S, Canato E, Pasut G, Montopoli M, Rüschoff J, Wild P, Moch H, De Bono J, and Alimonti A: CDCP1 overexpression drives prostate cancer progression and can be targeted in vivo. The Journal of Clinical Investigation 130: 2435-2450, 2020.

Before 2020 (Selected)

  1. Hirabayashi S, and Cagan R: Salt-inducible kinases mediate nutrient-sensing to link dietary sugar and tumorigenesis in Drosophila. eLife 4: e08501, 2015.
  2. Hirabayashi S, Baranski TJ, and Cagan R: Transformed Drosophila cells evade diet-mediated insulin resistance through wingless signaling. Cell 154: 664-675, 2013.
  3. Hirabayashi S, Nakagawa K, Sumita K, Hidaka S, Kawai T, Ikeda M, Kawata A, Ohno K, Hata Y: Threonine 74 of MOB1 is a putative key phosphorylation site by MST2 to form the scaffold to activate nuclear Dbf2-related kinase 1. Oncogene 27: 4281-4292., 2008.
  4. Hirabayashi S, Tajima M, Yao I, Nishimura W, Mori H, Hata Y: JAM4, a junctional cell adhesion molecule interacting with a tight junction protein, MAGI-1. Molecular and Cellular Biology 23: 4267-4282, 2003